POS1349 A BIOMARKER APPROACH TO DATA-DRIVEN IDENTIFICATION OF ENDOTYPES IN KNEE OA PATIENTS
Authors: Z. Lisowska-Petersen, M. Toft Hannani, M. Karsdal, C. Bager, A. C. Bay-Jensen, C. Thudium
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Osteoarthritis (OA) is a heterogeneous and multifactorial disease. Despite its high prevalence, the underlying mechanisms of disease are not fully understood, and treatment options are limited. One of the challenges in understanding OA is the lack of clear subgroups or "endotypes" within the disease, which could help to identify specific causes and point to more targeted treatments. Recent research has suggested that molecular biomarkers may be able to help identify different endotypes of OA. For example, certain biomarkers may be elevated in OA patients with inflammation, while others may be elevated in patients with more severe cartilage degeneration. <h3>Objectives</h3> The objective of the study was to identify endotypes of OA using soluble biomarkers reflecting tissue turnover by applying unsupervised machine learning approaches. <h3>Methods</h3> Biomarkers of cartilage remodeling (CTX-II, C2M, T2CM, PRO-C2), bone remodeling (N-MID, UCTX-I, SCTX-I), and tissue inflammation (CRPM, VICM, C1M, C3M) were measured at baseline in the phase III clinical trials SMC01 (n=1176) and SMC02 studies (n=1030), testing efficacy and safety of oral salmon calcitonin in knee OA patients. Only patients from the placebo group with more than 5 biomarkers available were included (n=528). Approximately 4% of data was missing data and imputed using Random Forest. K-Means clustering was applied on UMAP dimensionality reduced data. The association of change in symptomatic and radiographic parameters over 2 years with the identified clusters was compared with Kruskal Wallis test for numerical variables and chi-square test for categorical variables. <h3>Results</h3> K-Means clustering identified three distinct clusters; 1) a low tissue turnover endotype, 2) a systemic inflammation endotype and 3) A structural damage endotype (Figure 1). The structural damage endotype was characterized by higher levels of bone remodeling markers CTX-I, N-MID and the cartilage degradation marker CTX-II. The systemic inflammation endotype presented with higher levels of C1M, C2M, C3M, CRPM and VICM related to tissue inflammation. Finally, the low tissue turnover endotype showed overall lower levels of both tissue-related and inflammatory markers. We observed a difference in JSW change over two years between the three groups (Cluster 1: -0.28 mm, Cluster 2: -0.16 mm, Cluster 3: -0.32 mm; p=0.049), but this difference was not significant in the corrected analysis. Overall, the three endotypes progressed similarly. <h3>Conclusion</h3> These findings suggest that distinct biomarker-based endotypes exist in OA and highlight that multiple mechanistic avenues may lead to joint deterioration. By identifying these endotypes we may enable the development of more targeted treatments that are tailored towards the underlying cause of OA in individual subgroups of patients. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Zofia Lisowska-Petersen: None declared, Monica Toft Hannani: None declared, Morten Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, Cecilie Bager Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, Anne-Christine Bay-Jensen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, Christian Thudium Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience.